Potent and broadly neutralizing antibodies against sarbecoviruses elicited by single ancestral SARS-CoV-2 infection
Yu Lei, Yajie Wang, Yuanchen Liu, Xiaomin Xing, Chen Li, Xun Wang, Jialu Shi, Wentai Ma, Jiayan Li, Yanjia Chen, Rui Qiao, Xiaoyu Zhao, Shilei Tian, Ming Gao, Wen Shuhua, Yingxue Xue, Tianyi Qiu, Hongjie Yu, Yongjun Guan, Hin Chu, Lei Sun, Pengfei Wang
Abstract
The emergence of various SARS-CoV-2 variants presents challenges for antibody therapeutics, emphasizing the need for more potent and broadly neutralizing antibodies. Here, we employed an unbiased screening approach and successfully isolated two antibodies from individuals with only exposure to ancestral SARS-CoV-2. One of these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum of SARS-CoV-2 variants, including the latest KP.2, KP.3 and XEC, with consistent IC50 values ranging from ~1 to 5 ng/mL. It also displayed broad neutralization activity against SARS-CoV and related sarbecoviruses. Structural analysis revealed that these antibodies target shared hotspot but mutation-resistant epitopes, with their Fabs locking receptor binding domains (RBDs) in the “down” conformation through interactions with adjacent Fabs and RBDs, and cross-linking Spike trimers into di-trimers. In vivo studies conducted in a JN.1-infected hamster model validated the protective efficacy of CYFN1006-1. These findings suggest that antibodies with cross-neutralization activities can be identified from individuals with exclusively ancestral virus exposure. Functional and structural studies of two potent antibodies isolated from individuals exposed only to ancestral SARS-CoV-2, demonstrating broad neutralization against the latest SARS-CoV-2 variants and related sarbecoviruses.